The compound ponatinib (“compound 1”) is also known under the tradename Iclusig and was previously designated as AP24534. It is an FDA approved oral drug candidate developed by ARIAD Pharmaceuticals for the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL). Generally speaking, the multi-kinase inhibitor is known to be useful in the treatment of disorders associated with pathological cellular proliferation, such as neoplasms, cancer, and conditions associated with pathological angiogenesis. The compound is a multi-target tyrosine-kinase inhibitor [W S Huang et al. (2010); Journal of Medical Chemistry 53 (12): 4701-19].
The compound was also designated as “3-(2-Imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methylpiperazine-1-yl)methyl]-3-(trifluoromethyl)phenyl]benzamide” or as “3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)-methyl)-3-(trifluoromethyl)phenyl)benzamide”, depicted below:

The protein kinases are a large family of proteins which play a central role in the regulation of a wide variety of cellular processes. Abnormal protein kinase activity has been related to several disorders, ranging from non-life threatening diseases such as psoriasis to extremely serious diseases such as cancers. Several kinase inhibitors have been developed and used therapeutically with some important successes. However, not all of the targeted patients respond to those kinase inhibitors, and some become refractory to a given inhibitor through the emergence of mutation in the kinase or by other mechanisms.
The abnormal tyrosine kinase, BCR-ABL, is the hallmark of chronic myeloid leukemia (CML) and Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). Ponatinib is an oral, small-molecule pan-Bcr-Abl/Src protein inhibitor that is indicated in the US for the treatment of adults with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy, or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy.
WO 2007/075869 A2 describes the synthesis of ponatinib (Example 16). Equivalent U.S. Pat. No. 8,114,874 is cited in the FDA Orange Book for ponatinib. WO 2011/053938 A1 claims an oral formulation comprising ponatinib which can be used for the treatment of neoplasms, cancers and hyperproliferative disorders e.g. chronic myelogenous leukemia (CML). The document also describes the synthesis of ponatinib and its mono hydrochloride salt (pages 42-44 of the document). According to the disclosure, the hydrochloride salt of ponatinib was found to be an anhydrous crystalline solid.
It has now been found that although many additional different solid state forms of ponatinib can be produced (by selecting appropriate conditions), only very few of the additional solid state forms show desirable characteristics for a pharmaceutical product. Moreover, for one particular form, form I, the present inventors found that it was not available in sufficient purity, e.g. polymorphic purity, when its preparation was approached by standard, solution-based crystallization processes.
The present invention therefore relates to solid state forms of ponatinib hydrochloride which possess advantageous physical properties. The solid state form and the associated properties can be influenced by controlling the conditions under which ponatinib hydrochloride is obtained in solid form.
Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g. measured by thermogravimetric analysis—“TGA”, or differential scanning calorimetry—“DSC”), X-ray powder diffraction (XRPD or powder XRD) pattern, infrared absorption fingerprint, and solid state nuclear magnetic resonance (NMR) spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.
Discovering new polymorphic forms and solvates of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms. New polymorphic forms and solvates of a pharmaceutically useful compound or salts thereof can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., better processing or handling characteristics, improved dissolution profile, improved stability, improved purity, or improved shelf-life.
Typically ponatinib hydrochloride is administered orally, as this route provides comfort and convenience of dosing. Although salts of ponatinib and polymorphic forms thereof are known in the art, finding a good or even the optimal form with regard to bioavailability, inter-patient variability, and safety remains a considerable challenge, in particular when the compound forms many salts or polymorphic forms. Further, not all forms of ponatinib are equally suitable with regard to polymorphic and chemical stability, flow properties, compressibility, dissolution rate, and some are at least to some extent hygroscopic or show electrostatic charging. These properties can constitute disadvantages in the preparation of pharmaceutical compositions, such as tablets.
It is therefore an object of the present invention to provide solid state forms of ponatinib hydrochloride, as well as pharmaceutical compositions comprising the same, which do not show at least one or more of the above-described problematic properties. In particular, it is an object to provide solid state forms of ponatinib hydrochloride which show good bioavailability, low inter-patient variability, excellent overall therapeutic efficacy, excellent polymorphic and/or chemical stability, excellent flow properties, good compressibility, an excellent dissolution profile, and which are non-hygroscopic and/or do not electrostatically charge. The present inventors have found a solid state form of ponatinib hydrochloride which shows advantageous properties in at least one of the mentioned aspects.